Bartonella quintana (BQ) is a gram-negative human pathogen that causes serious and potentially fatal infections, and is the leading cause of culture-negative heart valve infection in the US. BQ also causes persistent bacteremia and fatal illness in immunocompromised individuals with cancer and HIV/AIDS. BQ is transmitted to humans by the body louse; humans become infected when the BQ bacteria in the louse feces are introduced into the louse bite wound by scratching. BQ alternates between two very different niches: the bloodstream of the homeothermic mammalian reservoir (37C) and the gut of the poikilothermic arthropod vector (28C). Virtually nothing is known about the virulence factors involved in the transition between the host and arthropod vector. However, the arthropod niche is an essential part of the life cycle of BQ, and it is required for infection of humans. To surviv and proliferate, BQ bacteria must adapt rapidly during the shift between these two disparate environments. Such adaptation to environmental changes and stresses are frequently mediated by alternative sigma factor subunits of the RNA polymerase. We found that rpoE, an uncharacterized sigma factor gene homologous to the extracytoplasmic function (ECF) sigma factor of several alpha-proteobacteria, is significantly up-regulated at the 28C temperature of the arthropod vector. In addition, rpoE is necessary for colonization of lice by BQ. Thus, BQ appears to have uniquely co-opted the alpha-proteobacterial general stress response system to up-regulate genes at 28C to adapt to its vector. Our long-term goal is to delineate the transcriptional program employed by the BQ pathogen to permit survival in the transition to, and within the arthropod niche, with the goal of identifying common regulatory themes and targets with potential applicability to other arthropod-borne bacterial pathogens. The short-term goal, and the focus of this proposal, is to identify the niche-specific genes involved in the transition between the arthropod and human host, and the regulatory network controlling their expression in BQ. The specific aims of this proposal are: 1) to determine the in vivo role of RpoE-directed transcription in colonization of the human body louse by BQ; and 2) to define the BQ RpoE regulon response to louse stressors in vitro, and identify RpoE-responsive promoter elements involved in the BQ human-louse transition. Successful completion of these specific aims will have a positive impact by: 1) identifying factors and regulatory networks that are necessary for pathogen transition between niches; 2) leveraging this knowledge to identify targets for preventive and therapeutic intervention in arthropod-borne pathogens; and 3) elucidating the unexplored and novel utilization of the alpha-proteobacterial ECF15 class of s factors for adaptation by the BQ human pathogen. Collectively, our preliminary data and the research proposed herein represent a new paradigm in sigma factor adaptive response for both the ECF15 s factor field, and the bacterial pathogenesis field.